Advanced therapy for pulmonary arterial hypertension due to congenital heart disease: a clinical perspective in a new therapeutic era

Cardiolog

Genomic Prediction in Maize Breeding Populations with Genotyping-by-Sequencing

Genotyping-by-sequencing (GBS) technologies have proven capacity for delivering large numbers of marker genotypes with potentially less ascertainment bias than standard single nucleotide polymorphism (SNP) arrays. Therefore, GBS has become an attractive alternative technology for genomic selection. However, the use of GBS data poses important challenges, and the accuracy of genomic prediction using GBS is currently undergoing investigation in several crops, including maize, wheat, and cassava. The main objective of this study was to evaluate various methods for incorporating GBS information and compare them with pedigree models for predicting genetic values of lines from two maize populations evaluated for different traits measured in different environments (experiments 1 and 2). Given that GBS data come with a large percentage of uncalled genotypes, we evaluated methods using nonimputed, imputed, and GBS-inferred haplotypes of different lengths (short or long). GBS and pedigree data were incorporated into statistical models using either the genomic best linear unbiased predictors (GBLUP) or the reproducing kernel Hilbert spaces (RKHS) regressions, and prediction accuracy was quantified using cross-validation methods. The following results were found: relative to pedigree or marker-only models, there were consistent gains in prediction accuracy by combining pedigree and GBS data; there was increased predictive ability when using imputed or nonimputed GBS data over inferred haplotype in experiment 1, or nonimputed GBS and information-based imputed short and long haplotypes, as compared to the other methods in experiment 2; the level of prediction accuracy achieved using GBS data in experiment 2 is comparable to those reported by previous authors who analyzed this data set using SNP arrays; and GBLUP and RKHS models with pedigree with nonimputed and imputed GBS data provided the best prediction correlations for the three traits in experiment 1, whereas for experiment 2 RKHS provided slightly better prediction than GBLUP for drought-stressed environments, and both models provided similar predictions in well-watered environments

Initiating maize pre-breeding programs using genomic selection to harness polygenic variation from landrace populations

BACKGROUND: The limited genetic diversity of elite maize germplasms raises concerns about the potential to breed for new challenges. Initiatives have been formed over the years to identify and utilize useful diversity from landraces to overcome this issue. The aim of this study was to evaluate the proposed designs to initiate a pre-breeding program within the Seeds of Discovery (SeeD) initiative with emphasis on harnessing polygenic variation from landraces using genomic selection. We evaluated these designs with stochastic simulation to provide decision support about the effect of several design factors on the quality of resulting (pre-bridging) germplasm. The evaluated design factors were: i) the approach to initiate a pre-breeding program from the selected landraces, doubled haploids of the selected landraces, or testcrosses of the elite hybrid and selected landraces, ii) the genetic parameters of landraces and phenotypes, and iii) logistical factors related to the size and management of a pre-breeding program. RESULTS: The results suggest a pre-breeding program should be initiated directly from landraces. Initiating from testcrosses leads to a rapid reconstruction of the elite donor genome during further improvement of the pre-bridging germplasm. The analysis of accuracy of genomic predictions across the various design factors indicate the power of genomic selection for pre-breeding programs with large genetic diversity and constrained resources for data recording. The joint effect of design factors was summarized with decision trees with easy to follow guidelines to optimize pre-breeding efforts of SeeD and similar initiatives. CONCLUSIONS: Results of this study provide guidelines for SeeD and similar initiatives on how to initiate pre-breeding programs that aim to harness polygenic variation from landraces. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2345-z) contains supplementary material, which is available to authorized users

Long-term outcome after an early invasive versus selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome and elevated cardiac troponin T (the ICTUS trial): a follow-up study.

Contains fulltext : 53227.pdf (publisher's version ) (Closed access)BACKGROUND: The ICTUS trial was a study that compared an early invasive with a selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome (nSTE-ACS). The study reported no difference between the strategies for frequency of death, myocardial infarction, or rehospitalisation after 1 year. We did a follow-up study to assess the effects of these treatment strategies after 4 years. METHODS: 1200 patients with nSTE-ACS and an elevated cardiac troponin were enrolled from 42 hospitals in the Netherlands. Patients were randomly assigned either to an early invasive strategy, including early routine catheterisation and revascularisation where appropriate, or to a more selective invasive strategy, where catheterisation was done if the patient had refractory angina or recurrent ischaemia. The main endpoints for the current follow-up study were death, recurrent myocardial infarction, or rehospitalisation for anginal symptoms within 3 years after randomisation, and cardiovascular mortality and all-cause mortality within 4 years. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN82153174. FINDINGS: The in-hospital revascularisation rate was 76% in the early invasive group and 40% in the selective invasive group. After 3 years, the cumulative rate for the combined endpoint was 30.0% in the early invasive group compared with 26.0% in the selective invasive group (hazard ratio 1.21; 95% CI 0.97-1.50; p=0.09). Myocardial infarction was more frequent in the early invasive strategy group (106 [18.3%] vs 69 [12.3%]; HR 1.61; 1.19-2.18; p=0.002). Rates of death or spontaneous myocardial infarction were not different (76 [14.3%] patients in the early invasive and 63 [11.2%] patients in the selective invasive strategy [HR 1.19; 0.86-1.67; p=0.30]). No difference in all-cause mortality (7.9%vs 7.7%; p=0.62) or cardiovascular mortality (4.5%vs 5.0%; p=0.97) was seen within 4 years. INTERPRETATION: Long-term follow-up of the ICTUS trial suggests that an early invasive strategy might not be better than a more selective invasive strategy in patients with nSTE-ACS and an elevated cardiac troponin, and implementation of either strategy might be acceptable in these patients

[Early invasive strategy no better than a selective invasive strategy for patients with non-ST-segment elevation acute coronary syndromes and elevated cardiac troponin T levels: long-term follow-up results of the ICTUS trial]

Contains fulltext : 69339.pdf (publisher's version ) (Closed access)OBJECTIVE: To determine whether routine coronary angiography followed by revascularisation where appropriate is better than initial drug treatment in patients with non-ST-segment elevation acute coronary syndromes (nSTE-ACS) and elevated troponin T concentrations. DESIGN: Multicentre randomised clinical trial (www.controlled-trials. com, number: SRCTN82153174). METHOD: Patients with nSTE-ACS and elevated cardiac troponin were randomly assigned to an early invasive strategy or a selective invasive strategy. The early invasive strategy consisted of coronary angiography and revascularisation as indicated within 48 hours. The selective invasive strategy consisted of initial drug therapy; catheterisation was performed if the patient developed refractory angina or recurrent ischaemia. The main endpoints were a composite of death, recurrent myocardial infarction and rehospitalisation for anginal symptoms within 3 years, and all-cause mortality within 4 years. RESULTS: A total of 1200 patients were enrolled from 42 hospitals in the Netherlands. The in-hospital revascularisation rate was 76% in the early invasive group and 40% in the selective invasive group. After 3 years, the cumulative rate for the composite endpoint was 30.0% in the early invasive group and 26.0% in the selective invasive group (hazard ratio 1.21; 95% CI: 0.97-1.50; p = 0.09). The 4-year all-cause mortality rate was similar in both treatment groups (7.9% vs 7.7%; p = 0.62). CONCLUSION: Long-term follow-up of this trial suggests that an early invasive strategy is not better than a selective invasive strategy in patients with nSTE-ACS and elevated cardiac troponin. Therefore, implementation of either strategy is acceptable in these patients